The incidence of HIV-1 infection continues to rise in populations throughout the world despite the development of candidate vaccines and highly active anti-retroviral therapy (I-IAART). It is now clear that HIV- I establishes a chronic infection in humans which the host immune system fails to eradicate despite the presence of HI V-specific cell mediated and humoral immune responses. HIV- 1 exploits various mechanisms in order to evade the immune system including the infection and killing of HIV-specific helper T-cells, the maintenance of a latent state and mutation of its immunogenic envelope protein, gp120. We propose that HIV-1 proteins such as gp120 interfere with immune cell migration allowing HIV-infected cells to escape challenge by host immune effector cells. We have recently demonstrated that resting T-cells move away from the chemokine, stromal-cell derived factor-I (SDF-1) and HIV-1IIIB gp120, in a CXCR4 receptor mediated and concentration dependent manner in vitro and in vivo. In addition, we showed that the intracellular signaling pathway for movement of resting T-cells away from both SDF-1 or HIV-1 gp120 was distinct from that for movement towards the chemokinetic agents. In view of these preliminary findings we intend to define the migratory responses to HIV-1 gp120 of immune effector cells which are known to be directly involved in the immune control of HJV infection in vivo. In this way we would propose to determine whether movement of immune effector cells away from HIV-1gp120 contributes to a novel mechanism by which HIV-1 evades the immune system. The proposal has three aims; 1) The characterization of the migratory response of activated T-cells, including HI V-specific cytotoxic lymphocytes (CTLs), and monocytes away from CCR5 binding chemokines and CCR5 binding HIV-1 gp120 using a number of established in vitro transmigration assays. 2) The biochemical characterization of the migration of immune effector cells away from CCR5 binding HIV-1 gp120 using a battery of signal transduction pathway inhibitors, mutants of the gp120 molecule and antibodies directed against gp120 and its chemokine co-receptor binding site 3). The definition of the role of HIV-l gp120 induced modulation of immune effector cell migration in vivo using animal model systems in which HIV-1 gp120 is expressed and modulation of the immune response to the WV -1 protein is quantitated. In these ways we hope to expand the understanding of why humans fail to contain HIV- 1 infection and to facilitate the design of novel therapies that will ultimately assist in the eradication of the virus in the HI V-infected individual.